6-170554285-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The 6-170554285-T-C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 152,254 control chromosomes in the GnomAD database, including 6,254 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (6250 hom., cov: 33)
  • Exomes 𝑓: 0.32 (4 hom.)
• Consequence: TBP ENST00000421512.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0280

Genes affected

TBP (HGNC:11588): (TATA-box binding protein) Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes TBP, the TATA-binding protein. A distinctive feature of TBP is a long string of glutamines in the N-terminus. This region of the protein modulates the DNA binding activity of the C terminus, and modulation of DNA binding affects the rate of transcription complex formation and initiation of transcription. The number of CAG repeats encoding the polyglutamine tract is usually 25-42, and expansion of the number of repeats to 45-66 increases the length of the polyglutamine string and is associated with spinocerebellar ataxia 17, a neurodegenerative disorder classified as a polyglutamine disease. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBP	ENST00000421512.5			upstream_gene_variant		1
TBP	ENST00000540980.5			upstream_gene_variant		2		A2

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39511 AN: 152062 Hom.: 6251 Cov.: 33

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.729

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.272

GnomAD4 exome AF: 0.324 AC: 24 AN: 74 Hom.: 4 Cov.: 0 AF XY: 0.280 AC XY: 14 AN XY: 50

Gnomad4 AFR exome AF: 0.500

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0833

Gnomad4 NFE exome AF: 0.375

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.260 AC: 39510 AN: 152180 Hom.: 6250 Cov.: 33 AF XY: 0.261 AC XY: 19444 AN XY: 74400

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.273

Gnomad4 ASJ AF: 0.229

Gnomad4 EAS AF: 0.729

Gnomad4 SAS AF: 0.345

Gnomad4 FIN AF: 0.268

Gnomad4 NFE AF: 0.298

Gnomad4 OTH AF: 0.275

Alfa AF: 0.267 Hom.: 2739

Bravo AF: 0.261

Asia WGS AF: 0.487 AC: 1691 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.48
Dann	Benign	0.30

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2179373; hg19: chr6-170863373;